We hypothesize that activation of T regulatory (T reg) cells constitutes an essential and common element of the pathway that creates peripheral allograft tolerance. We will test the hypothesis that: (i) the speed with which T reg cells expand after Ag activation and (ii) the pool size and potency of counteracting alloaggressive T cells are the variables that determine whether rejection or tolerance will occur. The overall aim of this proposal is to full define the role, phenotype, molecular mechanism of action, limitations of T reg cells in governing the allograft response.